Beginning in 1998, a surge of new agents has expanded treatment options for rheumatoid arthritis (RA) patients. Although the disease modifying potential of these agents is encouraging, their use must be weighed against an evolving array of new safety concerns. Because of the popularity of these agents with patients and rheumatologists alike, clinicians must be prepared to discuss the potential risks associated with novel disease-modifying antirheumatic drugs and biologic therapies as they begin to appear with greater frequency in practice. This article discusses the safety issues arising from clinical trial and postmarketing experience with several new and commonly used agents, with specific emphasis on adalimumab, etanercept, infliximab, anakinra, and leflunomide.